Three-years of dalbavancin use at a UK tertiary referral hospital serving a population with high numbers of people who inject drugs

Abstract Background Dalbavancin’s unique properties have led to an increase in its off-licence use in complex infection and in vulnerable populations including people who inject drugs (PWID), but data remain limited. In this retrospective cohort study, we describe the characteristics, treatment rationale and outcomes for all adult inpatients treated with dalbavancin at a UK tertiary hospital. Results Fifty-eight inpatients were treated with dalbavancin between 1 January 2018 and 1 January 2021, 98.3% for off-licence diagnoses. Acute bacterial skin and skin structure infection, infective endocarditis and endovascular infections were each diagnosed in 22.4% of patients. Bone and joint infections were diagnosed in 18.9%, discitis in 12.1% and central line-associated bloodstream infections in 5.2%. Sixty-nine percent of patients were bacteraemic; 52.5% Staphylococcus aureus, 5.0% MRSA. Two mild adverse reactions were attributed to dalbavancin. Treatment was successful in 43 (75.4%) patients, and failed in seven (12.3%). Seven (12.3%) were lost to follow-up. Thirty-five patients (60.3%) were PWID, with low median age (41.0 years) and Charlson Comorbidity scores (0). Self-discharge was taken by 17.1% of PWID, and 20.6% were lost to follow-up. At 90 days, three (8.6%) PWID were deceased. Conclusions In this first UK cohort, dalbavancin was used off licence and in persons facing barriers to conventional therapies. Where data is available, it was safe and effective. Dalbavancin appears a potentially valuable tool in improving outcomes for PWID.


Background
2][3] Dalbavancin is a semisynthetic lipoglycopeptide with activity against staphylococci, streptococci and vancomycin-susceptible enterococci.The lipophilic side chains confer the long terminal half-life of 8.5 days. 4ike Europe and the USA, in the UK dalbavancin is licenced for the treatment of acute bacterial skin and skin structure infection (ABSSSI) in non-pregnant adults caused by susceptible Gram-positive bacteria including MRSA.Studies have demonstrated it is well tolerated and safe, 5 and it can reduce the length of inpatient stays and associated costs. 6Owing to its unique properties, the off-licence use of dalbavancin in complex infections has increased, particularly in those facing barriers to conventional management.However, data remain limited. 7n 2018, when our study began, an estimated 1.3 million adults had high-risk opioid use in the European Union, with the highest prevalence in the UK at 0.82%. 8People who inject drugs (PWID) are disproportionately affected by bacterial infections, most commonly due to Gram-positive organisms.][11] This first published UK cohort describes the characteristics, clinical management and outcomes for adult inpatients treated with dalbavancin over 3 years at a tertiary hospital serving a population including high numbers of PWID.

Study design and procedures
treatments are at the discretion of an infection specialist.There are no dedicated infection services for PWID.
Pharmacy records identified sequential inpatients for whom dalbavancin was ordered between 1 January 2018 and 1 January 2021.Patients were included if they were aged 18 years or above, admitted to hospital during the study period, and received dalbavancin for an acute infection episode.Patients receiving multiple courses of dalbavancin were included for each distinct infection.Absence of necessary data excluded patients.
Data were collected on patient characteristics, inpatient investigations, clinical diagnoses, management, dalbavancin treatment rationale and goals.Inpatient and infection episodes outcomes were extracted, and all-cause mortality recorded 90 days after first dalbavancin dose.Anonymized data were managed and analysed in Microsoft Excel v. 16.66.

Ethical considerations
Non-identifiable data were collected to maximize the anonymity of the cohort.As a retrospective review, patient care was not affected.In accordance with the University Hospitals Sussex Trust Research and Development department, and with the NHS Health Research Authority, this study did not necessitate ethical approval.

Definitions and statistical methods
Patient sex was the biological sex recorded in clinical notes.A Charlson Comorbidity Index Score was calculated to reflect prognostic comorbidity as described elsewhere. 13'Insecure accommodation' was recorded for those who were homeless, sofa surfing or staying in hostels.All inpatient diagnoses were recorded as defined by the treating physicians.'Endovascular infection' includes permanent-pacemaker infection.Microbiological diagnosis was when a pathogen considered causative of the infection episode treated with dalbavancin was identified.Surgical intervention includes any procedure relating to the infection episode.Antimicrobial therapy other than dalbavancin was quantified by 'days of therapy' (DOT) as defined elsewhere. 14Categories for dalbavancin rationale include 'healthcare worker concerns around long-term intravenous access', 'patient conduct on ward', 'non-adherence to conventional therapy', 'antimicrobial contraindications', 'palliative approach' and 'barriers to conventional therapy'.The last group was heterogenous, including drug interactions, unstable housing, accessibility and cognitive barriers.
The outcome of treatment with dalbavancin was assessed by the data-collecting study physicians (C.B., K.B., C.H.) at 90 days after first dose.Where possible, patients' hospital, Summary Care Records and, where deceased, death certificates were accessed.Treatment was considered a 'success' if there were no additional treatments nor admissions relating to the infection episode treated with dalbavancin.Where followup was planned, contact with a healthcare professional without documented concern ongoing.Treatment was considered a 'failure' if the criteria for success where not met.In the case of death, failure was recorded if the causes of death related to infection treated with dalbavancin.'Lost to follow-up' was applied where follow-up was planned within the 90-day period and there was no evidence of assessment by a healthcare professional.Where no data were accessible after discharge, outcomes were considered 'unknown'.These definitions were independent of patient compliance with planned therapies.Where the treatment outcome was in doubt, the data-collecting physicians conferred and, if necessary, referred to a third senior study physician (B.D. or S.S.).Adverse reactions to dalbavancin were as per the Medicines and Healthcare products Regulatory Agency definition and identified by the study physicians collecting data. 15nalyses were descriptive, providing frequencies and proportions for categorical variables, and medians with their IQR for continuous variables with skewed distributions.Data disaggregated by history of intravenous drug use are presented.Persons with current or history of illicit intravenous drug use within the previous 12 months were included in the PWID group due to the shared risk of complicated infections with metastatic seeding due to a higher likelihood of abnormal anatomy, as well as comparable rationale for dalbavancin use.

Results
Baseline patient characteristics are presented in Table 1, and diagnoses, clinical management and outcomes are presented in Table 2. Table 3 presents the data for patients for whom therapy with dalbavancin failed.

Clinical management
All patients received antimicrobials prior to dalbavancin, with a median of 3.0 (IQR 2.0-4.0)agents for a median 18.0 DOT (IQR 7.0-28.0).Fifty-seven (98.3%) patients received dalbavancin off licence, often for more than one indication.Forty (69.0%) patients had a captured bacteraemia.Microbiological data are presented in Table 2.The most common diagnoses were ABSSSI, infective endocarditis (IE) and endovascular infection, each diagnosed in 13 (22.4%)patients.
The rationale for using dalbavancin include 'barriers to conventional therapy' (n = 26; 46.4%), 'healthcare worker concerns around long-term IV access' (n = 25; 44.6%), 'patient conduct on the ward' (n = 14; 25.0%) and 'non-adherence to conventional therapy' (n = 13; 23.2%).These are presented by history of intravenous drug use in Table 2. Two patients had 'other' reasons for dalbavancin use; both native valve IE patients, dalbavancin was used due to failed conventional therapies.
Regarding dalbavancin treatment, 55 (94.8%) patients received their first dose as an inpatient.Thirty-five (60.3%) patients had a planned second dose; just over half (n = 18 [51.4%])received this as an outpatient, 10 (28.6) as an inpatient and seven (20%) did not attend.The given doses followed the first by a median of 8.0 (IQR 7.0-8.0)days.Four (6.9%) patients received a third dose and one patient a fourth, all as outpatients a median of 35.5 (IQR 29.5-48.3)and 42.0 days after their first doses A further patient missed a planned fourth dose.The median cumulative dalbavancin dose per patient was 1500 mg (n = 56, IQR 1500-3000) given over a median of 1.0 doses (IQR 1.0-2.0).A total of eight (13.8%)patients missed one or more planned dalbavancin dose.Dalbavancin was given in combination with other antimicrobials for 14 patients (24.1%).

Adverse reactions to dalbavancin
Two patients (3.4%) had an adverse reaction to dalbavancin; one patient experienced phlebitis following their first dalbavancin dose then tolerated their second, another developed drug-induced neutropaenia to a trough of 0.8 × 10 9 /L, which was successfully treated with granulocyte colony-stimulating factor.

Outcomes
While alive at 90 days, the treatment outcome could not be determined for one patient repatriated to a hospital outside of the Trust.Of the fifty-seven (98.3%) patients with known outcomes, 43 (75.4%) had treatment success.Treatment failed for seven (12.3%) patients, and a further seven were LTF.
Ninety days following their first dalbavancin dose, six patients (10.3%) had died.For four of these patients' treatment was considered a success and their deaths unrelated to the infection episode.Three patients were PWID whose unexpected community deaths where each determined to be drug-related by the coroner.The fourth patient was not a PWID, and managed with dalbavancin palliatively.Causes of death were unrelated to infection and its treatment.Treatment was considered a 'failure' in two cases, neither PWID, both had expected inpatient deaths.One was a 53-year-old with a Charlson Comorbidity Index Score of five treated with dalbavancin empirically for an ABSSSI and IE with palliative rationale after a new diagnosis of metastatic pancreatic cancer.ABSSSI and IE were given as causes of death.The second patient was a 75-year-old with a Charlson Comorbidity Index Score of five treated for a Streptococcus oralis bacteraemia and prosthetic valve IE.Dalbavancin was chosen palliatively due  Three-years of real-world dalbavancin use in the UK    Data for the seven patients for whom treatment failed are presented in Table 3.Three (42.9%) were PWID.The two cases who died (28.6% of total cases of failure) have already been described.Of patients who failed treatment, fewer had a microbiological diagnosis (three; 42.9% compared with 46; 79.3%) and received previous antibiotics for fewer DOT (9.0 (IQR 5.0-14.0) to 18.0 (IQR 7.0-28.0)).A similar proportion missed a planned dose of dalbavancin.Of the six patients who failed therapy and were discharged, four were readmitted for the same infection episode (4/57; 1.8%).
All eight missed dalbavancin doses (22.9%) were in PWID.The length of admission was shorter for PWID [median 14.0 (IQR 9.5-19.0)days compared with 26.0 days (IQR 10.5-49.5)]and all self-discharges were in this group.The median number of days to discharge following their first dalbavancin dose was 0 (IQR 0-3.0) for PWID compared with 4.0 (IQR 0-11.0)days in the non-PWID group.All seven patients lost to follow-up were in PWID (n = 7; 21.2%).Three of the deaths within 90 days of dalbavancin therapy were in PWID.The dalbavancin treatment outcome for all of these patients was a success and their deaths unrelated.
For the whole cohort, n = 7 unless otherwise stated; for the non-PWID group n = 4 unless otherwise stated; for the PWID group n = 3 unless otherwise stated.CLABSI, central line-associated bloodstream infection; ABX, antibiotics.

Bresges et al.
published UK data on the use of dalbavancin for off-licence indications, and for PWID outside of the USA.Nearly all dalbavancin prescriptions in our study were off licence.The most frequent indications were bacteraemia (69.0% of the cohort), ABSSSI, IE and endovascular infection (each diagnosed in 22.4%).With significant heterogeneity, it is difficult to compare studies.In a contemporary 2-year Spanish cohort the most common diagnoses were similar; orthopaedic infections (28.3%),ABSSSIs (22.5%) and cardiovascular infections (20.9%). 16redictably from dalbavancin's Gram-positive activity, in our study and others, S. aureus was the most commonly isolated organism.However, rates of MRSA varied significantly.Of our cohort 8.6% were known MRSA colonized and 8.7 of S. aureus bacteraemias were MRSA.This reflects the 7.3% of isolates recorded for the UK by the European Antimicrobial Resistance Surveillance Network (EARS-Net) in 2018. 29All studies including PWID have been conducted in the USA, with MRSA rates between 25% 17 and 88%. 18Our study therefore presents useful data on the use of dalbavancin in a low MRSA prevalence context, particularly in PWID.
Unsurprisingly for an agent used off licence, all patients in our cohort received alternative antibiotics before dalbavancin.Previous antibiotic prevalence was high in similar studies; 77.8% 19 to 100%. 20,30Beyond this, the significant variations in treatment reflects the lack of consensus around dalbavancin regimens, especially for off-licence indications, as well as the heterogeneity of studies' populations and diagnostic indications.Interestingly, a 2020 study where 39.8% of dalbavancin indications were off licence and 62% empirical, found that previous or concomitant antibiotics did not improve the probability of clinical cure using models adjusted for age, comorbidities and site of infection. 19espite being used off licence, dalbavancin caused few (two; 3.4%) adverse reactions, comparable with similar studies. 6,16,20- 22,30The Morata et al. study including significant off-licence prescription did not find any difference in safety at sub-analysis by patient characteristics nor pathogens. 16This is encouraging for future use of dalbavancin in a varied population.
Disappointingly a substantial number of our cohort (n = 7/58; 12.7%) were LTF.No patients without a history of intravenous drug use were lost to our follow-up in versus 21.2% of PWID, a group for whom this is a recognized challenge. 9In comparable studies without PWID, LTF rates range between 3% 21 and 24.7%. 19In reporting studies which include PWID, the proportions LTF are higher, between 15% and 31%. 17,18,23,24eterogeneity in studies' definitions, populations, representation of PWID, diagnostic indications, follow-up periods and finally the lack of direct comparators, all make efficacy assessments difficult.Few studies have compared dalbavancin with the standard of care for off-licence indications.Of such studies, similar outcomes were seen with dalbavancin when treating osteomyelitis, 25,31 and the broader indication of invasive Gram-positive infections. 21More favourable outcomes were seen in for central line-associated bloodstream infections. 26Our outcome data relating to success, failure and LTF are broadly in line with other studies including PWID. 17,18,23,24While the small numbers limit useful comparison, it is worth noting that PWID were not overrepresented in the seven of our cohort who 'failed' treatment.Over 13% of our cohort missed a planned dalbavancin dose.Despite similar treatment outcomes at 90 days, this does raise concerns for drug-resistance in the long-term; an area in need of further study in this context.

People who inject drugs
PWID represent most of our cohort (60.3%); a population where data is especially sparce.3][34] The UK Health Security Agency's 2018 cross-sectional survey of PWID reported demographics closely reflecting our cohort, suggesting broader generalisability within the UK. 35In our study PWID were younger, had fewer comorbidities, but increased rates of depression, HCV and unstable housing: all recognized associations. 10,1134,36 Although dalbavancin followed comparable therapy, the rationales for its use were different for PWID.For PWID barriers to conventional care often related to intravenous drug use, indeed at the RSCH this history almost excludes outpatient parenteral therapy (OPAT).23,33 Studies on OPAT efficacy and safety have found rates of antibiotic completion, line tampering and catheter-associated infections to be comparable in PWID. 10,11e note the higher self-discharge rate of 17.1% seen in PWID.0][11] This is concerning as unplanned discharges are associated with high rates of readmission, longer subsequent stays and higher 30 day mortality. 10Comparative outcome data would be of particular interest in this area.
It is interesting that the time to discharge following the last dose of dalbavancin was shorter in PWID; 0 (IQR 0-3.0) days compared with 4.0 (IQR 0-11.0)days.This hints at the role of dalbavancin in facilitating discharge in a young population with low comorbidity scores.Earlier discharge may also be accommodated by the move towards early switch from intravenous to oral antimicrobials, as can be seen in the OVIVA, POET and SABATO trials.However, evidence about the efficacy of early oral antimicrobial switch in PWIDs remains limited and there are concerns about compliance with oral treatment postdischarge and effective follow-up.][39] When those of our cohort LTF are excluded, treatment success and failure rates for PWID become more comparable to those without this history; success rates of 88.5% (n = 23/26) to 82.6% (19/23) and failure rates of 11.5% (n = 3/26) to 17.4% (4/23) respectively.Similar to the non-PWID group, the 8.6% 90 day mortality in PWID is strikingly in view of their young ages and low comorbidity scores.A recent matched cohort study of people with a history of illicit opioid use in England found them to have excess risk of death across all major causes of death analysed.In their cohort with a median age of 35.1 years and followup period of 8.7 years, 12.4% died. 40

Study limitations
Set in a hospital providing District General Hospital as well as tertiary referral hospital services outside of London, these data are probably generalizable to many UK institutions.However, this generalisability is limited by its retrospective and single-centre design.The small participant numbers and currently limited role for dalbavancin will have introduced further bias.We sought to limit selection bias by consecutive recruitment over a 3-year period.The exclusion of outpatient cases and the control of dalbavancin prescription by infection specialists at the RSCH probably biased diagnostic representation.No one in our cohort was living with HIV, and we did not collect data on immunosuppressed states except diabetes.All our patients were treated with antimicrobials before dalbavancin, which must be considered when evaluating efficacy.As there is no standard, various dosing and combination regimens were used for our cohort, limiting the generalisability of efficacy.Whereas we present data on given and missed dalbavancin doses, we did not include planned durations of therapy as this information was usually unavailable.This limits conclusions.The lack of a comparator group makes comparative efficacy assessment impossible.Our study was weakened by the unknown outcome for one patient.The most significant weakness in our study data is the large numbers LTF.Unfortunately, this is common among PWID and highlights the challenges in caring for this population.We did not collect data on the causes of death in our patients which limits inference.Finally, the study period included the years COVID-19 most disrupted hospital and community health care and undoubtedly influenced our findings.

Conclusions
This cohort offers the first comprehensive review of the realworld experience of dalbavancin use in a UK secondary care setting over a 3-year period.The high proportion of off-licence prescriptions and use in PWID adds to the limited evidence in these areas.Our findings suggest that dalbavancin appears safe and effective when applied to complex infections, particularly when there are barriers to conventional care models.Dalbavancin is a potentially valuable tool in what must be a multifaceted effort to improve the treatment and outcomes for PWID.Further research is required to assess the efficacy, safety, optimal treatment regimens, implications for antimicrobial resistance and healthcare costs of dalbavancin's real-life use, including in PWID.

Table 1 .
The baseline characteristics of adult inpatients treated with dalbavancin over a 3-year period at a large teaching hospital in Brighton

Table 2 .
The diagnoses, clinical management and outcomes of adult inpatients treated with dalbavancin over a 3-year period at a large teaching hospital in Brighton ContinuedBresges et al.

Table 2 .
ContinuedData are presented for the whole cohort, for PWID and for those without a history of illicit intravenous drug use (non-PWID).For the whole cohort n = 58 unless otherwise stated; for the PWID group n = 23 unless otherwise stated; for the non-PWID group n = 35 unless otherwise stated.CLABSI, central line-associated bloodstream infection; ABX, antibiotics.

Table 3 .
The baseline characteristics diagnoses, clinical management and outcomes of adult inpatients whose treatment with dalbavancin 'failed' over a 3-year period at a large teaching hospital in Brighton